SUMMARY Amylin and amylin formed aggregates are distinct: one is a gut-brain hormone via the physiological pathway, the other one is a factor for diabetes via the pathological pathway. Pramlintide is an amylin analog without aggregating character and a diabetes drug approved by the Food and Drug Administration (FDA). Recent studies suggest that pramlintide has the potential to be repositioned for Alzheimer's disease (AD). As a human clinical trial of pramlintide for AD is costly and time-consuming, we propose to use quantitative systems pharmacology (QSP) to characterize the genotypic and phenotypic changes influenced by pramlintide that will be informative for a go/no-go decision on a large phase II/III clinical trial. The central hypothesis for our proposed study is that pramlintide will enhance the physiological amylin-amylin receptor (AmR) pathway via cognate AmR to reduce AD pathology and increase synapsis in the brain, and thus improve cognition. This will be a combined study of computational analysis and translational approach with three specific aims. Aim 1 will use existing data to conduct a systems biology analysis to characterize the amylin-AmR pathway for AD. Aim 2 will use cells and AD mouse models to conduct a proof-of-principle study of the effects of pramlintide on the amylin-AmR pathway. Aim 3 will use human subjects to conduct a proof-of- principle study of the effects of pramlintide on the amylin-AmR pathway. Should our proposed study support the concept that pramlintide to be repositioned for AD, it will lay foundation for a clinical trial on the drug for AD.